Helicobacter pylori CagA targets gastric tumor suppressor RUNX3 for proteasome-mediated degradation.
Helicobacter pylori CagA targets gastric tumor suppressor RUNX3 for proteasome-mediated degradation.
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DOI：
10.1038/onc.2010.304
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发表时间：
2010-10-14
期刊：
影响因子：
8
通讯作者：
Chen, L. F.
中科院分区：
文献类型：
--
作者：
Tsang, Y. H.;Lamb, A.;Romero-Gallo, J.;Huang, B.;Ito, K.;Peek, R. M., Jr.;Ito, Y.;Chen, L. F.
慢性感染caga阳性幽门螺杆菌是胃腺癌发生的最强危险因素。cagA基因产物cagA被注射到胃上皮细胞中，通过与多种细胞信号分子的物理相互作用和失调来干扰细胞功能。RUNX3是多种组织中的肿瘤抑制因子，在胃癌中经常失活。在这项研究中，我们发现幽门螺旋杆菌感染以caga依赖的方式使胃肿瘤抑制因子RUNX3失活。通过CagA的WW结构域对RUNX3的PY基序的特异性识别，CagA直接与RUNX3结合。CagA WW结构域的缺失或RUNX3中PY基序的突变，会使CagA诱导RUNX3泛素化和降解的能力丧失，从而丧失其抑制RUNX3转录激活的能力。我们的研究发现RUNX3是幽门螺杆菌CagA的一个新的细胞靶点，并揭示了CagA通过阻断胃肿瘤抑制因子RUNX3的活性而作为癌蛋白发挥作用的机制。
Chronic infection with cagA-positive Helicobacter pylori is the strongest risk factor for the development of gastric adenocarcinoma. The cagA gene product CagA is injected into gastric epithelial cells and disturbs cellular functions by physically interacting with and deregulating a variety of cellular signaling molecules. RUNX3 is a tumor suppressor in many tissues, and it is frequently inactivated in gastric cancer. In this study, we show that H. pylori infection inactivates the gastric tumor suppressor RUNX3 in a CagA-dependent manner. CagA directly associates with RUNX3 through a specific recognition of the PY motif of RUNX3 by a WW domain of CagA. Deletion of the WW domains of CagA or mutation of the PY motif in RUNX3 abolishes the ability of CagA to induce the ubiquitination and degradation of RUNX3, thereby extinguishing its ability to inhibit the transcriptional activation of RUNX3. Our studies identify RUNX3 as a novel cellular target of H. pylori CagA and also reveal a mechanism by which CagA functions as an oncoprotein by blocking the activity of gastric tumor suppressor RUNX3.
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